beta-alkylcholine salts and their acyl esters



Y ll higher homologues.

Patented Mar. 12, 1940 atent angers fi-ALKYLCHOLINE SALTS AND THEIR ACYLESTERS Randolph '1. Major, Plainfield, and Howard 'T. Bonnett, Rahway,N. .l., assignors to, Merck 1&5 Co. Inc., Rahway, N. J., a corporationof New Jersey i No Drawing. Original application December 4,

1935, Serial No.52,872. Dividedand this application November 1, 1937,Serial No. 172,240

4 Claims. (01. 260 -584) This application is'a division of our copendingapplication Serial No. 52,872, filed December 4, 1935, which issued onNovember 8, 1938, as Patent No. 2,135,521. This invention relates to Icertain higher homologues of beta-methy1 choline halide and to theprocess for their production.

The co-pending application of one of us, Randolph T. Major, inassociation with Joseph K.

Cline, Serial No. 733,604, filed July 13, 1934, which issued on May 12,1936, as Patent No. 2,040,146,

relates to the preparation of acetyhfi-methylcholine chloride. We havenow succeeded in producing, as well, its hitherto unknown The generalseries of the B-n-alkyl choline halides which are the subject of thepresent in vention have been tested pharmacologically with interestingresults. It has been found that,

50 while the acyl derivatives of these new compounds exhibit generally amuscarine action similar to that of acetyl-B-methylcholine chloride, thenon acylated higher homologues exhibit rather unexpected and important(inferences in their 25 therapeutic action. Thus. for instance, Whilethe B-hexylcholine and the fl-heptylcholine chlorides exhibit amuscarine action, the fi-propylcholine and the fi-butylcholine chloridesexhibit the typical, so-called nicotinic action which is a 80 matter ofconsiderable practical therapeutic interest.

Broadly, the process of the present invention" relatively lowerhomologues in question, as for instance, fi-ethylcholine chloride,B-n-propyl- '50 choline chloride, etc., may be prepared directly bytreating the appropriately selected chlorhydrin with trimethylamine,thus avoiding the intermediate step of forming the methiodide.

While either modification of the above de- 55 scribed method may beemployed, for the prepa- The ration of all of the homologues hereincontemplated, it has been found more convenient, because of the rapidincrease in hygroscopicity with increase in size of the allryl group, toprepare the higher homologues by means of the reaction of methyl iodideon dimethylamino-alkanol, so that the necessary purification may be morereadily effected.

The appropriate chlorhydrins used as starting materials in each instanceWBIG prepared by the reaction of chloroacetaldehyde with the selectedGrignard reagent. The hitherto unreported l-chlorononanol-Z, was alsoprepared in this Way.

During the working out of our process a number of intermediate compoundswere prepared which had not previously been described; these include1-dimethylarnino-butano1-2, l-dimethylamino-pentanol-Z,1dimethylamine-hexanol2, 1-dimethylamineoctanol-2, and1-dimethylamino-nonanol-Z.

The following description of the more detailed steps of the processexemplifies specific adaptations of the general method set forth aboveto the ultimate production of various specific acetyl-e-alkylcholinehalides, which are embraced within the scope of our invention.

Preparation of 1-dimethylaminoallc0mol-2.-' The appropriate chlorohydrinis heated with a solution of two male. of dimethylamine in benzone at115-120 C. for about hours, and isolated from the resulting mixture bythe usual methods. The compounds obtained are mobile, colorless liquidspossessing a strong amine-like odor. 1-dimethylamino-butanol-Z andl-dimethylamino-pentanol-2 are very soluble in water, but the higherhomologues are insoluble in water; all of the compounds are soluble inthe usual organic solvents.

Preparation of c-n-alkylcholinc iodide.-The methiodides of the1-dimethylamino-alkanol-Z compounds are prepared by treating the latterwith methyl iodide at room temperature. They are recrystallized fromWarm acetone to which ether is added, and occur in the form ofnonhygroscopic white, micro-crystalline solids. Preparation of,B-n-alkylcholine chZoride.-The p-n-alkyicholine iodides are convertedto their corresponding chlorides by reacting upon them with AgCl inalcoholic solution by the methods of Jones and Major (Jour. Am. Chem.Soc, 52, 309-1930). The silver salts formed inthe reaction are removedby filtration, and the 5-halkylcholine chloride is precipitated by theaddition of anhydrous ether to the filtrate. The

last traces of silver chloride are removed by adding the precipitate toasaturated solution of alkylcholine iodides, chlorides shown on the sameline in the other columns of the table.

Ohlorohydrins Alkyl R (CHa)2NCHzCHOH-R (GHa)aNICH2CHOH-R(CH3)3NC1CHzCHOH-R 1-chlorobutanol-2 P. 142144 C. 760/mm, M. P. 1623 CM. P. l746 C. l-chloropentano1-2 P. 7374 C. 30/nin1 M. P. 198200 C M. P.115- C. 1-chlor0heXanol-2 P. 8990 C. 25/m1n. M. P. 9092 C... M. P.100.5102 C 1-ch10r0heptanol-2. P. 8385 C. 1l/Inm. M. P. 98l00 O. M. P.7274 C. l-chloro-octanol-2 P. 99l01 C. l0/mm M. P. 109-110 C. M. P.69-71 C. l-chlorononanol-Z P. l04106 G. 5/mm M; P. l22.5l23.5 C M. I.9799 O.

hydrogen sulfide in absolute alcohol. Activated harcoal is added and themixture filtered.

p-ethylcholine chloride may be recrystallized from butyl alcohol,B-propylcholine may be recrystallized from a mixture of 'butyl alcoholand isopropyl ether and ,B-butylcholine may be recrys-tallized withdifficulty from a mixture of butyl alcohol and benzene. The remainingcompounds are obtained in the form of gums which crystallize on standingin a desiccator. The final products are obtained in the form of white,extremely hygroscopic solids.

Examples for the production of other products of this series can bereadily derived by reference to the table given below, with theselection of any given chlorhydrin shown in the first column of thetable, and its treatment with dimethylamine by the modified steps of theprocess outlined in detail above, will produce, respectively, thecorresponding dimethylamino-alkanols, beta-n- According' to the othermodifications of our process, as mentioned above, for the preparation ofc-ethyl, fl-propyl and ,B-butyl choline chloride,

trimethylamine is'co-ndensed with the appropriate chlorhydrin in benzenesolution at 110 C. for about 24 hours. The resulting choline chloridesare precipitated by the addition of ether and recrystallized fromorganic solvents as indicated.

We claim as our invention:-

1. A product of the group consisting of p-ethylcholine chloride,fl-ethyl choline iodide, B-n-propyl choline iodide, ,B-n-butylcholineiodide, p-n-hexylcholine iodide, p-n-hexylcholine chloride,fi-nheptylcholine iodide, and fi-n-heptylcholine chloride.

2. B-ethylcho-line iodide. 3. p-n-propylcholine iodide.

e-n-heptylcholine chloride.

RANDOLPH T. MAJOR. HOWARD T. BONNETT.

